Endocrine therapy in metastatic breast cancer-more than just CDK4/6 inhibitors

Abstract

Advanced hormone receptor-positive breast cancer is one of the women’s most common malignant diseases and remains incurable despite recent therapeutic innovations. The dependence of hormone receptor-positive breast cancer on hormonal growth signals offers the possibility of inhibiting this signaling pathway using anti-hormonal therapy. Nevertheless, the development of resistance to antitumoral drugs remains a challenge. Molecularly-targeted substances significantly improve survival rates and (as in the case of cyclin-dependent kinase 4 and 6 inhibitors) are widely used in clinical practice and enhance endocrine therapy’s efficacy. Agents such as everolimus, alpelisib, and capivasertib target the phosphoinositide 3 kinase/protein kinase B/mammalian target of rapamycin pathway, which is a promising approach to overcoming endocrine resistance. Novel therapies are being studied in numerous trials, and some already show significant benefits in survival rates. The development of new therapies to avert endocrine resistance is an urgent challenge in modern medicine. The following review will examine some promising therapeutic approaches.

Keywords

Advanced hormone receptor-positive breast cancer / endocrine resistance / CDK4/6 inhibitor / molecularly-targeted substances

References

[1] Fitzmaurice C,Barber RM.Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015: a systematic analysis for the global burden of disease study.JAMA Oncol2017;3:524-48 PMCID:PMC6103527

[2] Sørlie T,Tibshirani R.Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications.Proc Natl Acad Sci USA2001;98:10869-74 PMCID:PMC58566

[3] Buzdar AU.Endocrine therapy in the treatment of metastatic breast cancer.Semin Oncol2001;28:291-304

[4] O’Leary B,Turner NC.Treating cancer with selective CDK4/6 inhibitors.Nat Rev Clin Oncol2016;13:417-30

[5] Li Z,Zhang J.Mechanisms of CDK4/6 inhibitor resistance in luminal breast cancer.Front Pharmacol2020;11:580251 PMCID:PMC7751736

[6] Martin M,Ruiz-Borrego M.Palbociclib in combination with endocrine therapy versus capecitabine in hormonal receptor-positive, human epidermal growth factor 2-negative, aromatase inhibitor-resistant metastatic breast cancer: a phase III randomised controlled trial-PEARL.Ann Oncol2021;32:488-99

[7] Park YH,Kim GM.Palbociclib plus exemestane with gonadotropin-releasing hormone agonist versus capecitabine in premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer (KCSG-BR15-10): a multicentre, open-label, randomised, phase 2 trial.Lancet Oncol2019;20:1750-9

[8] Finn RS,Lang I.The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study.Lancet Oncol2015;16:25-35

[9] Finn RS,Rugo HS.Palbociclib and letrozole in advanced breast cancer.N Engl J Med2016;375:1925-36

[10] Tripathy D,Colleoni M.Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial.Lancet Oncol2018;19:904-15

[11] Hortobagyi GN,Burris HA.Overall survival with ribociclib plus letrozole in advanced breast cancer.N Engl J Med2022;386:942-50

[12] Johnston S,Di Leo A.MONARCH 3 final PFS: a randomized study of abemaciclib as initial therapy for advanced breast cancer.NPJ Breast Cancer2019;5:5 PMCID:PMC6336880

[13] Hortobagyi GN,Burris HA.Ribociclib as first-line therapy for HR-positive, advanced breast cancer.N Engl J Med2016;375:1738-48

[14] Im SA,Bardia A.Overall survival with ribociclib plus endocrine therapy in breast cancer.N Engl J Med2019;381:307-16

[15] Slamon DJ,Chia S.Overall survival with ribociclib plus fulvestrant in advanced breast cancer.N Engl J Med2020;382:514-24

[16] Goetz MP,Campone M.MONARCH 3: abemaciclib as initial therapy for advanced breast cancer.J Clin Oncol2017;35:3638-46

[17] Li J,Zhao F.Association of cyclin-dependent kinases 4 and 6 inhibitors with survival in patients with hormone receptor-positive metastatic breast cancer: a systematic review and meta-analysis.JAMA Netw Open2020;3:e2020312 PMCID:PMC8094425

[18] Hortobagyi GN,Burris HA.Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer.Ann Oncol2018;29:1541-7

[19] Seidman AD,Fehrenbacher L.National cancer institute breast cancer steering committee working group report on meaningful and appropriate end points for clinical trials in metastatic breast cancer.J Clin Oncol2018;36:3259-68 PMCID:PMC7351338

[20] Rugo HS,Diéras V.Palbociclib plus letrozole as first-line therapy in estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer with extended follow-up.Breast Cancer Res Treat2019;174:719-29 PMCID:PMC6438948

[21] Finn RS,Dieras VC.Overall survival (OS) with first-line palbociclib plus letrozole (PAL+LET) versus placebo plus letrozole (PBO+LET) in women with estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer (ER+/HER2- ABC): analyses from PALOMA-2.JCO2022;40:LBA1003

[22] Pfizer. Pfizer announces overall survival results from phase 3 PALOMA-2 trial of IBRANCE® (palbociclib) for the first-line treatment of ER+, HER2- metastatic breast cancer. Available from: www.pfizer.com/news/press-release/press-release-detail/pfizer-announces-overall-survival-results-phase-3-paloma-2 [Last accessed on 16 Feb 2023]

[23] Helwick, caroline. paloma-2: no overall survival benefit reported with palbociclib/letrozole in Advanced breast cancer. The ASCO post. Available from: https://ascopost.com/issues/august-10-2022/no-overall-survival-benefit-reported-with-palbociclibletrozole-in-advanced-breast-cancer/ [Last accessed on 16 Feb 2023]

[24] Turner NC,Ro J.Overall survival with palbociclib and fulvestrant in advanced breast cancer.N Engl J Med2018;379:1926-36

[25] Cristofanilli M,Im S.Overall survival (OS) with palbociclib (PAL) + fulvestrant (FUL) in women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC): updated analyses from PALOMA-3.JCO2021;39:1000

[26] Sledge GW Jr,Neven P.The effect of abemaciclib plus fulvestrant on overall survival in hormone receptor-positive, ERBB2-negative breast cancer that progressed on endocrine therapy-MONARCH 2: a randomized clinical trial.JAMA Oncol2020;6:116-24 PMCID:PMC6777264

[27] Cardoso F,Senkus E.5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5).Ann Oncol2020;31:1623-49 PMCID:PMC7510449

[28] Lu YS,Colleoni M.Updated overall survival of ribociclib plus endocrine therapy versus endocrine therapy alone in pre- and perimenopausal patients with HR+/HER2- advanced breast cancer in MONALEESA-7: a phase III randomized clinical trial.Clin Cancer Res2022;28:851-9 PMCID:PMC9377723

[29] Neven P,Tolaney SM.Abemaciclib plus fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer in premenopausal women: subgroup analysis from the MONARCH 2 trial.Breast Cancer Res2021;23:87 PMCID:PMC8381581

[30] Herrera-Abreu MT,Asghar U.Early adaptation and acquired resistance to CDK4/6 inhibition in estrogen receptor-positive breast cancer.Cancer Res2016;76:2301-13

[31] Pandey K,Kim SK.Molecular mechanisms of resistance to CDK4/6 inhibitors in breast cancer: a review.Int J Cancer2019;145:1179-88 PMCID:PMC6767051

[32] Portman N,Carson E,Lim E.Overcoming CDK4/6 inhibitor resistance in ER-positive breast cancer.Endocr Relat Cancer2019;26:R15-30

[33] Gao X,Wang H.Cyclin D-CDK4/6 functions in cancer.Adv Cancer Res2020;148:147-69

[34] Yu Q,Geng Y.Requirement for CDK4 kinase function in breast cancer.Cancer Cell2006;9:23-32

[35] Choi YJ,Hydbring P.The requirement for cyclin D function in tumor maintenance.Cancer Cell2012;22:438-51 PMCID:PMC3487466

[36] Yang C,Bhatt T.Acquired CDK6 amplification promotes breast cancer resistance to CDK4/6 inhibitors and loss of ER signaling and dependence.Oncogene2017;36:2255-64 PMCID:PMC5393973

[37] Miller TW,Garrett JT.Mutations in the phosphatidylinositol 3-kinase pathway: role in tumor progression and therapeutic implications in breast cancer.Breast Cancer Res2011;13:224 PMCID:PMC3315683

[38] Wander SA,Zangardi ML.Clinical outcomes with abemaciclib after prior CDK4/6 inhibitor progression in breast cancer: a multicenter experience.J Natl Compr Cancer Netw2021;1-8

[39] Dickler MN,Rugo HS.MONARCH 1, a phase II study of abemaciclib, a CDK4 and CDK6 inhibitor, as a single agent, in patients with refractory HR+/HER2- metastatic breast cancer.Clin Cancer Res2017;23:5218-24

[40] Kalinsky K,Chiuzan C.A randomized, phase II trial of fulvestrant or exemestane with or without ribociclib after progression on anti-estrogen therapy plus cyclin-dependent kinase 4/6 inhibition (CDK 4/6i) in patients (pts) with unresectable or hormone receptor-positive (HR+), HER2-negative metastatic breast cancer (MBC): MAINTAIN trial.JCO2022;40:LBA1004

[41] Hermida-Prado F.The ESR1 mutations: from bedside to bench to bedside.Cancer Res2021;81:537-8

[42] Brett JO,Bardia A.ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-positive breast cancer.Breast Cancer Res2021;23:85 PMCID:PMC8365900

[43] Jeselsohn R,De Angelis C,Schiff R.ESR1 mutations-a mechanism for acquired endocrine resistance in breast cancer.Nat Rev Clin Oncol2015;12:573-83 PMCID:PMC4911210

[44] Jeselsohn R,Buchwalter G.Emergence of constitutively active estrogen receptor-α mutations in pretreated advanced estrogen receptor-positive breast cancer.Clin Cancer Res2014;20:1757-67 PMCID:PMC3998833

[45] Turner NC,Kilburn L.ESR1 mutations and overall survival on fulvestrant versus exemestane in advanced hormone receptor-positive breast cancer: a combined analysis of the phase III SoFEA and EFECT trials.Clin Cancer Res2020;26:5172-7

[46] Fribbens C,Kilburn L.Plasma ESR1 mutations and the treatment of estrogen receptor-positive advanced breast cancer.J Clin Oncol2016;34:2961-8

[47] Toy W,Won H.ESR1 ligand-binding domain mutations in hormone-resistant breast cancer.Nat Genet2013;45:1439-45 PMCID:PMC3903423

[48] Schiavon G,Garcia-Murillas I.Analysis of ESR1 mutation in circulating tumor DNA demonstrates evolution during therapy for metastatic breast cancer.Sci Transl Med2015;7:313ra182 PMCID:PMC4998737

[49] Forshew T,Parkinson C.Noninvasive identification and monitoring of cancer mutations by targeted deep sequencing of plasma DNA.Sci Transl Med2012;4:136ra68

[50] Dawson SJ,Murtaza M.Analysis of circulating tumor DNA to monitor metastatic breast cancer.N Engl J Med2013;368:1199-209

[51] Turner NC,André F.Palbociclib in Hormone-receptor-positive advanced breast cancer.N Engl J Med2015;373:209-19

[52] Berger F,Delaloge S.Randomised, open-label, multicentric phase III trial to evaluate the safety and efficacy of palbociclib in combination with endocrine therapy, guided by ESR1 mutation monitoring in oestrogen receptor-positive, HER2-negative metastatic breast cancer patients: study design of PADA-1.BMJ Open2022;12:e055821 PMCID:PMC8896060

[53] Bidard F,Bachelot T.Abstract GS3-05: fulvestrant-palbociclib vs continuing aromatase inhibitor-palbociclib upon detection of circulating ESR1 mutation in HR+ HER2- metastatic breast cancer patients: results of PADA-1, a UCBG-GINECO randomized phase 3 trial.Cancer Res2022;82:GS3-05

[54] Delaloge S,Bachelot T.First line aromatase inhibitor (AI) + palbociclib with randomized switch to fulvestrant + palbociclib upon detection of circulating ESR1 mutation in HR+ HER2-metastatic breast cancer patients: Global safety results of PADA-1, a UCBG-GINECO phase III trial.Cancer Res2022;82:P1-18-16

[55] Carlson RW.The history and mechanism of action of fulvestrant.Clin Breast Cancer2005;6:S5-8

[56] Pike AC,Walton J.Structural insights into the mode of action of a pure antiestrogen.Structure2001;9:145-53

[57] Toy W,Razavi P.Activating ESR1 mutations differentially affect the efficacy of ER antagonists.Cancer Discov2017;7:277-87 PMCID:PMC5340622

[58] Fanning SW.Next-generation ERα inhibitors for endocrine-resistant ER+ breast cancer.Endocrinology2019;160:759-69

[59] Bidard FC,Neven P.Elacestrant (oral selective estrogen receptor degrader) versus standard endocrine therapy for estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: results from the randomized phase III EMERALD trial.J Clin Oncol2022;40:3246-56 PMCID:PMC9553388

[60] Bihani T,Arlt H.Elacestrant (RAD1901), a selective estrogen receptor degrader (SERD), has antitumor activity in multiple ER+ breast cancer patient-derived xenograft models.Clin Cancer Res2017;23:4793-804

[61] Wardell SE,Chao CA,McDonnell DP.Evaluation of the pharmacological activities of RAD1901, a selective estrogen receptor degrader.Endocr Relat Cancer2015;22:713-24 PMCID:PMC4545300

[62] Garner F,Paquin D,Hattersley G.RAD1901: a novel, orally bioavailable selective estrogen receptor degrader that demonstrates antitumor activity in breast cancer xenograft models.Anticancer Drugs2015;26:948-56 PMCID:PMC4560273

[63] Martin Jimenez M,Chavez Mac Gregor M.211MO giredestrant (GDC-9545) vs physician choice of endocrine monotherapy (PCET) in patients (pts) with ER+, HER2- locally advanced/metastatic breast cancer (LA/mBC): primary analysis of the phase II, randomised, open-label acelERA BC study.Ann Oncol2022;33:S633-4

[64] Tolaney S,Petrakova K.212MO AMEERA-3, a phase II study of amcenestrant (AMC) versus endocrine treatment of physician’s choice (TPC) in patients (pts) with endocrine-resistant ER+/HER2- advanced breast cancer (aBC).Ann Oncol2022;33:S634-5

[65] Linden HM,Bardia A.Abstract PD8-08: a phase 1/2 study of SAR439859, an oral selective estrogen receptor (ER) degrader (SERD), as monotherapy and in combination with other anti-cancer therapies in postmenopausal women with ER-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC): AMEERA-1.Cancer Res2021;81:PD8-08

[66] Bardia A,Ulaner GA.Dose-escalation study of SAR439859, an oral selective estrogen receptor (ER) degrader (SERD), in postmenopausal women with ER+/HER2- metastatic breast cancer (mBC).JCO2019;37:1054

[67] Bardia A,Hurvitz SA.AMEERA-5: a randomized, double-blind phase 3 study of amcenestrant plus palbociclib versus letrozole plus palbociclib for previously untreated ER+/HER2- advanced breast cancer.Ther Adv Med Oncol2022;14:17588359221083956 PMCID:PMC8928355

[68] Sanofi provides update on amcenestrant clinical development program - sanofi. Available from: https://www.sanofi.com/en/media-room/press-releases/2022/2022-08-17-05-30-00-2499668 [Last accessed on 16 Feb 2023]

[69] Rusquec P, Blonz C, Frenel JS, Campone M. Targeting the PI3K/Akt/mTOR pathway in estrogen-receptor positive HER2 negative advanced breast cancer.Ther Adv Med Oncol2020;12:1758835920940939 PMCID:PMC7388095

[70] Thangavel C,Ertel A.Therapeutically activating RB: reestablishing cell cycle control in endocrine therapy-resistant breast cancer.Endocr Relat Cancer2011;18:333-45 PMCID:PMC3624623

[71] Baselga J,Piccart M.Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer.N Engl J Med2012;366:520-9

[72] Beck JT,Campone M.Everolimus plus exemestane as first-line therapy in HR⁺, HER2^- advanced breast cancer in BOLERO-2.Breast Cancer Res Treat2014;143:459-67 PMCID:PMC3907668

[73] Yardley DA,Pritchard KI.Everolimus plus exemestane in postmenopausal patients with HR+ breast cancer: BOLERO-2 final progression-free survival analysis.Adv Ther2013;30:870-84 PMCID:PMC3898123

[74] Piccart M,Campone M.Everolimus plus exemestane for hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: overall survival results from BOLERO-2.Ann Oncol2014;25:2357-62 PMCID:PMC6267855

[75] Im YH,Lee KS.Safety and efficacy of everolimus (EVE) plus exemestane (EXE) in postmenopausal women with locally advanced or metastatic breast cancer: final results from EVEREXES.Breast Cancer Res Treat2021;188:77-89

[76] Lousberg L.Safety, efficacy and patient acceptability of everolimus in the treatment of breast cancer.Breast Cancer2016;10:239-52 PMCID:PMC5214808

[77] Mo H,Moore HCF.Real-world outcomes of everolimus and exemestane for the treatment of metastatic hormone receptor-positive breast cancer in patients previously treated with CDK4/6 inhibitors.Clin Breast Cancer2022;22:143-8

[78] Cook MM,Kaempf AJ,Savin MA.Everolimus plus exemestane treatment in patients with metastatic hormone receptor-positive breast cancer previously treated with CDK4/6 inhibitor therapy.Oncologist2021;26:101-6 PMCID:PMC7873317

[79] Jeong H,Kim JE,Jung KH.Comparison of the effectiveness and clinical outcome of everolimus followed by CDK4/6 inhibitors with the opposite treatment sequence in hormone receptor-positive, HER2-negative metastatic breast cancer.Cancer Res Treat2022;54:469-77 PMCID:PMC9016296

[80] Wolff AC,Bondarenko I.Randomized phase III placebo-controlled trial of letrozole plus oral temsirolimus as first-line endocrine therapy in postmenopausal women with locally advanced or metastatic breast cancer.J Clin Oncol2013;31:195-202

[81] Vinayak S.mTOR inhibitors in the treatment of breast cancer.Oncology2013;27:38-44

[82] Gökmen-Polar Y,Toroni RA.Investigational drug MLN0128, a novel TORC1/2 inhibitor, demonstrates potent oral antitumor activity in human breast cancer xenograft models.Breast Cancer Res Treat2012;136:673-82

[83] Zeng Z,Qiu YH.MLN0128, a novel mTOR kinase inhibitor, disrupts survival signaling and triggers apoptosis in AML and AML stem/ progenitor cells.Oncotarget2016;7:55083-97 PMCID:PMC5342403

[84] Zhang X,Xu T,Shen Z.Targeting of mTORC2 may have advantages over selective targeting of mTORC1 in the treatment of malignant pheochromocytoma.Tumour Biol2015;36:5273-81

[85] Zou Z,Yang J.Targeted inhibition of rictor/mTORC2 in cancer treatment: a new era after rapamycin.Curr Cancer Drug Targets2016;16:288-304

[86] García-Sáenz JÁ,Cubedo R.Sapanisertib plus fulvestrant in postmenopausal women with estrogen receptor-positive/HER2-negative advanced breast cancer after progression on aromatase inhibitor.Clin Cancer Res2022;28:1107-16 PMCID:PMC9365359

[87] Genome Atlas Network. Comprehensive molecular portraits of human breast tumours.Nature2012;490:61-70 PMCID:PMC3465532

[88] Goncalves MD,Cantley LC.Phosphatidylinositol 3-kinase, growth disorders, and cancer.N Engl J Med2018;379:2052-62

[89] Bosch A,Bergamaschi A.PI3K inhibition results in enhanced estrogen receptor function and dependence in hormone receptor-positive breast cancer.Sci Transl Med2015;7:283ra51

[90] Dent S,Im YH.Phase III randomized study of taselisib or placebo with fulvestrant in estrogen receptor-positive, PIK3CA-mutant, HER2-negative, advanced breast cancer: the SANDPIPER trial.Ann Oncol2021;32:197-207 PMCID:PMC8457522

[91] Baselga J,Iwata H.Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial.Lancet Oncol2017;18:904-16 PMCID:PMC5549667

[92] Krop IE,Ganju V.Pictilisib for oestrogen receptor-positive, aromatase inhibitor-resistant, advanced or metastatic breast cancer (FERGI): a randomised, double-blind, placebo-controlled, phase 2 trial.Lancet Oncol2016;17:811-21 PMCID:PMC5524539

[93] André F,Rubovszky G.Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer.N Engl J Med2019;380:1929-40

[94] Juric D,Rubovszky G.Abstract GS3-08: alpelisib + fulvestrant for advanced breast cancer: subgroup analyses from the phase III SOLAR-1 trial.Cancer Res2019;79:GS3-08

[95] André F,Juric D.Alpelisib plus fulvestrant for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: final overall survival results from SOLAR-1.Ann Oncol2021;32:208-17

[96] Rugo HS,Ciruelos E.Alpelisib plus fulvestrant in PIK3CA-mutated, hormone receptor-positive advanced breast cancer after a CDK4/6 inhibitor (BYLieve): one cohort of a phase 2, multicentre, open-label, non-comparative study.Lancet Oncol2021;22:489-98

[97] Turner S,Kanakamedala H.Effectiveness of alpelisib + fulvestrant compared with real-world standard treatment among patients with HR+, HER2-, PIK3CA-mutated breast cancer.Oncologist2021;26:e1133-42 PMCID:PMC8265362

[98] Hopkins BD,Du X.Suppression of insulin feedback enhances the efficacy of PI3K inhibitors.Nature2018;560:499-503

[99] Michaloglou C,Siersbaek R.Combined inhibition of mTOR and CDK4/6 is required for optimal blockade of E2F function and long-term growth inhibition in estrogen receptor-positive breast cancer.Mol Cancer Ther2018;17:908-20 PMCID:PMC6485624

[100] Vora SR,Kim N.CDK4/6 inhibitors sensitize PIK3CA mutant breast cancer to PI3K inhibitors.Cancer Cell2014;26:136-49

[101] Salmena L,Pandolfi PP.Tenets of PTEN tumor suppression.Cell2008;133:403-14

[102] Bertucci F,Patsouris A.Genomic characterization of metastatic breast cancers.Nature2019;569:560-4

[103] Carbognin L,Paris I.Prognostic and predictive implications of PTEN in breast cancer: unfulfilled promises but intriguing perspectives.Cancers2019;11:1401 PMCID:PMC6769721

[104] Costa C,Ly A.PTEN loss mediates clinical cross-resistance to CDK4/6 and PI3Kα inhibitors in breast cancer.Cancer Discov2020;10:72-85

[105] Juric D,Griffith M.Convergent loss of PTEN leads to clinical resistance to a PI3Kα inhibitor.Nature2015;518:240-4 PMCID:PMC4326538

[106] Stemke-Hale K,Lluch A.An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer.Cancer Res2008;68:6084-91 PMCID:PMC2680495

[107] Kalinsky K,McCourt CK.Effect of capivasertib in patients with an AKT1 E17K-mutated tumor: NCI-MATCH subprotocol EAY131-Y nonrandomized trial.JAMA Oncol2021;7:271-8 PMCID:PMC7774047

[108] Smyth LM,Meric-Bernstam F.Selective AKT kinase inhibitor capivasertib in combination with fulvestrant in PTEN-mutant ER-positive metastatic breast cancer.NPJ Breast Cancer2021;7:44 PMCID:PMC8052445

[109] Jones RH,Carucci M.Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive breast cancer (FAKTION): a multicentre, randomised, controlled, phase 2 trial.Lancet Oncol2020;21:345-57

[110] Smyth LM,Oliveira M.Capivasertib, an AKT kinase inhibitor, as monotherapy or in combination with fulvestrant in patients with AKT1 (E17K)-mutant, ER-positive metastatic breast cancer.Clin Cancer Res2020;26:3947-57 PMCID:PMC7415507

[111] Howell SJ,Carucci M.Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive, HER2-negative breast cancer (FAKTION): overall survival, updated progression-free survival, and expanded biomarker analysis from a randomised, phase 2 trial.Lancet Oncol2022;23:851-64

[112] Razavi P,Xu G.The genomic landscape of endocrine-resistant advanced breast cancers.Cancer Cell2018;34:427-438.e6 PMCID:PMC6327853

[113] Malone KE,Doody DR.Prevalence and predictors of BRCA1 and BRCA2 mutations in a population-based study of breast cancer in white and black American women ages 35 to 64 years.Cancer Res2006;66:8297-308

[114] Kurian AW,John EM.Performance of prediction models for BRCA mutation carriage in three racial/ethnic groups: findings from the Northern California Breast Cancer Family Registry.Cancer Epidemiol Biomarkers Prev2009;18:1084-91 PMCID:PMC2706699

[115] Antoniou AC,Soucy P.Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers.Breast Cancer Res2012;14:R33

[116] Mavaddat N,Andrulis IL.Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).Cancer Epidemiol Biomarkers Prev2012;21:134-47 PMCID:PMC3272407

[117] Ray-Coquard I,Pignata S.Olaparib plus bevacizumab as first-line maintenance in ovarian cancer.N Engl J Med2019;381:2416-28

[118] Moore K,Scambia G.Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer.N Engl J Med2018;379:2495-505

[119] Pujade-Lauraine E,Selle F.Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial.Lancet Oncol2017;18:1274-84

[120] Robson M,Senkus E.Olaparib for metastatic breast cancer in patients with a germline BRCA mutation.N Engl J Med2017;377:523-33

[121] Robson ME,Conte P.OlympiAD final overall survival and tolerability results: olaparib versus chemotherapy treatment of physician’s choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer.Ann Oncol2019;30:558-66 PMCID:PMC6503629

[122] Litton JK,Ettl J.Talazoparib in patients with advanced breast cancer and a germline BRCA mutation.N Engl J Med2018;379:753-63

[123] Lee KH,Goodwin A.Talazoparib versus chemotherapy in patients with HER2-negative advanced breast cancer and a germline BRCA1/2 mutation enrolled in Asian countries: exploratory subgroup analysis of the phase III EMBRACA trial.Cancer Res Treat2021;53:1084-95 PMCID:PMC8524025

[124] Tung NM,Ventz S.TBCRC 048: phase II study of olaparib for metastatic breast cancer and mutations in homologous recombination-related genes.J Clin Oncol2020;38:4274-82

[125] Bruno L,Waisberg F.Cyclin-dependent kinase 4/6 inhibitor outcomes in patients with advanced breast cancer carrying germline pathogenic variants in DNA repair-related genes.JCO Precis Oncol2022;6:e2100140

[126] Connolly R.Epigenetics as a therapeutic target in breast cancer.J Mammary Gland Biol Neoplasia2012;17:191-204 PMCID:PMC3515719

[127] Trapani D,Criscitiello C.Entinostat for the treatment of breast cancer.Expert Opin Investig Drugs2017;26:965-71

[128] Saito A,Mariko Y.A synthetic inhibitor of histone deacetylase, MS-27-275, with marked in vivo antitumor activity against human tumors.Proc Natl Acad Sci USA1999;96:4592-7 PMCID:PMC16377

[129] Connolly RM,Piekarz R.Entinostat: a promising treatment option for patients with advanced breast cancer.Future Oncol2017;13:1137-48 PMCID:PMC5618943

[130] Shah P,Sabnis G.Histone deacetylase inhibitor entinostat reverses epithelial to mesenchymal transition of breast cancer cells by reversing the repression of E-cadherin.Breast Cancer Res Treat2014;143:99-111

[131] Connolly RM,Miller KD.E2112: randomized phase III trial of endocrine therapy plus entinostat or placebo in hormone receptor-positive advanced breast cancer. a trial of the ECOG-ACRIN cancer research group.J Clin Oncol2021;39:3171-81

[132] Xu B,Hu X.Abstract GS1-06: a randomized control phase III trial of entinostat, a once weekly, class I selective histone deacetylase inhibitor, in combination with exemestane in patients with hormone receptor positive advanced breast cancer.Cancer Res2022;82:GS1-06

[133] Yardley DA,Melichar B.Randomized phase II, double-blind, placebo-controlled study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic estrogen receptor-positive breast cancer progressing on treatment with a nonsteroidal aromatase inhibitor.J Clin Oncol2013;31:2128-35 PMCID:PMC4881332

[134] Lee J,Pearson T,Ordentlich P.Abstract P5-21-15: the synergistic antitumor activity of entinostat (MS-275) in combination with palbociclib (PD 0332991) in estrogen receptor-positive and triple-negative breast cancer.Cancer Res2018;78:P5-21

[135] Finn RS,Bondarenko I.Overall survival results from the randomized phase 2 study of palbociclib in combination with letrozole versus letrozole alone for first-line treatment of ER+/HER2- advanced breast cancer (PALOMA-1, TRIO-18).Breast Cancer Res Treat2020;183:419-28 PMCID:PMC7383036

[136] Cristofanilli M,Bondarenko I.Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial.Lancet Oncol2016;17:425-39

[137] Sledge GW Jr,Neven P.MONARCH 2: abemaciclib in combination with fulvestrant in women with HR+/HER2- advanced breast cancer who had progressed while receiving endocrine therapy.J Clin Oncol2017;35:2875-84

[138] Slamon DJ,Chia S.Phase III randomized study of ribociclib and fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: MONALEESA-3.J Clin Oncol2018;36:2465-72

[139] Slamon DJ,Chia S.Ribociclib plus fulvestrant for postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer in the phase III randomized MONALEESA-3 trial: updated overall survival.Ann Oncol2021;32:1015-24

[140] Rugo HS,García-Sáenz JA.Management of abemaciclib-associated adverse events in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: safety analysis of MONARCH 2 and MONARCH 3.Oncologist2021;26:e53-65

[141] Turner NC,Bardia A.persevERA breast cancer (BC): phase III study evaluating the efficacy and safety of giredestrant (GDC-9545) + palbociclib versus letrozole + palbociclib in patients (pts) with estrogen-receptor-positive, HER2-negative locally advanced or metastatic BC (ER+/HER2- LA/mBC).JCO2021;39:TPS1103

[142] Im S,Llombart Cussac A.SERENA-4: A phase 3 comparison of AZD9833 (camizestrant) plus palbociclib, versus anastrozole plus palbociclib, for patients with ER-positive, HER2-negative advanced breast cancer who have not previously received systemic treatment for advanced disease.JCO2021;39:TPS1101